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CARING FOR THE

CRITICALLY ILL PATIENT

Higher vs Lower Positive End-Expiratory Pressure


in Patients With Acute Lung Injury
and Acute Respiratory Distress Syndrome
Systematic Review and Meta-analysis
Matthias Briel, MD, MSc
Maureen Meade, MD, MSc
Alain Mercat, MD
Roy G. Brower, MD
Daniel Talmor, MD, MPH
Stephen D. Walter, PhD
Arthur S. Slutsky, MD
Eleanor Pullenayegum, PhD
Qi Zhou, PhD
Deborah Cook, MD, MSc
Laurent Brochard, MD
Jean-Christophe M. Richard, MD
Francois Lamontagne, MD
Neera Bhatnagar, MLIS
Thomas E. Stewart, MD
Gordon Guyatt, MD, MSc

ROTECTING LUNGS FROM VENTIlation-induced injury is an important principle in the management of patients with acute
lung injury or acute respiratory distress
syndrome (ARDS). Although the critical care community has generally endorsed lower tidal volumes and inspiratory pressures, the optimal level of
positive end-expiratory pressure (PEEP)
remains unestablished.1,2 Experimental
data suggest that PEEP levels exceeding traditional values of 5 to 12 cm H2O
can minimize cyclical alveolar collapse
and corresponding shearing injury to the
lungs in patients with considerable
edema and alveolar collapse.3-5 For patients with relatively mild acute lung in-

See also p 883 and Patient Page.

Context Trials comparing higher vs lower levels of positive end-expiratory pressure


(PEEP) in adults with acute lung injury or acute respiratory distress syndrome (ARDS)
have been underpowered to detect small but potentially important effects on mortality or to explore subgroup differences.
Objectives To evaluate the association of higher vs lower PEEP with patientimportant outcomes in adults with acute lung injury or ARDS who are receiving ventilation with low tidal volumes and to investigate whether these associations differ across
prespecified subgroups.
Data Sources Search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (1996-January 2010) plus a hand search of conference proceedings (2004January 2010).
Study Selection Two reviewers independently screened articles to identify studies
randomly assigning adults with acute lung injury or ARDS to treatment with higher vs
lower PEEP (with low tidal volume ventilation) and also reporting mortality.
Data Extraction Data from 2299 individual patients in 3 trials were analyzed using
uniform outcome definitions. Prespecified effect modifiers were tested using multivariable hierarchical regression, adjusting for important prognostic factors and clustering effects.
Results There were 374 hospital deaths in 1136 patients (32.9%) assigned to
treatment with higher PEEP and 409 hospital deaths in 1163 patients (35.2%)
assigned to lower PEEP (adjusted relative risk [RR], 0.94; 95% confidence interval
[CI], 0.86-1.04; P = .25). Treatment effects varied with the presence or absence of
ARDS, defined by a value of 200 mm Hg or less for the ratio of partial pressure of
oxygen to fraction of inspired oxygen concentration (P = .02 for interaction). In
patients with ARDS (n = 1892), there were 324 hospital deaths (34.1%) in the
higher PEEP group and 368 (39.1%) in the lower PEEP group (adjusted RR, 0.90;
95% CI, 0.81-1.00; P = .049); in patients without ARDS (n = 404), there were 50
hospital deaths (27.2%) in the higher PEEP group and 44 (19.4%) in the lower
PEEP group (adjusted RR, 1.37; 95% CI, 0.98-1.92; P=.07). Rates of pneumothorax and vasopressor use were similar.
Conclusions Treatment with higher vs lower levels of PEEP was not associated with
improved hospital survival. However, higher levels were associated with improved survival among the subgroup of patients with ARDS.
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JAMA. 2010;303(9):865-873

jury, however, potential adverse consequences of higher PEEP levels, including


circulatory depression6 or lung overdistension,7 may outweigh the benefits. Several multicenter, randomized trials testing the incremental effect of higher levels

2010 American Medical Association. All rights reserved.

Author Affiliations are listed at the end of this article.


Corresponding Author: Maureen Meade, MD, MSc,
Department of Clinical Epidemiology and Biostatistics, Room 2C12, 1200 Main St W, Hamilton, ON L8N
3Z5, Canada (meadema@hhsc.ca).
Caring for the Critically Ill Patient Section Editor: Derek
C. Angus, MD, MPH, Contributing Editor, JAMA
(angusdc@upmc.edu).

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865

POSITIVE END-EXPIRATORY PRESSURE IN ACUTE LUNG INJURY AND ARDS

of PEEP were confounded by baseline


imbalances in prognostic factors and underpowered to rule in or rule out an important survival effect.8-10
Meta-analysis of individual-patient
data offers important advantages over
conventional meta-analysis, including standardized definitions and analyses across studies, adjustment for variations in individual patient prognosis at
baseline, and more powerful investigations of subgroup effects.11 In this systematic review and meta-analysis of individual-patient data, we investigated
the association between higher vs lower
PEEP levels and patient-important outcomes among adults with acute lung injury or ARDS who receive ventilation
with low tidal volumes; we also investigated whether effects differ across prespecified patient subgroups.
METHODS
Trial Selection and Data Collection

The predefined protocol for this metaanalysis of individual-patient data is available from the authors on request. Randomized trials eligible for this review
compared higher with lower levels of
PEEP (mean difference of at least 3 cm
H2O between groups during first 3 days
following randomization) in critically ill
adults (16 years) with a diagnosis of
acute lung injury or ARDS as defined by
the American-European Consensus Conference.12 Eligible trials incorporated a
target tidal volume of less than 8 mL/kg
of predicted body weight in both the experimental and the control ventilation
strategies and provided patient follow-up to death or for at least 20 days.
We identified eligible trials by an
electronic search of MEDLINE,
EMBASE, and the Cochrane Central
Register of Controlled Trials (all from
1996 to January 2010) using the terms
positive end-expiratory pressure*, PEEP,
low tidal volume*, open lung strateg*,
acute respiratory distress, acute lung injur*, and ards as text words and positive pressure respiration, tidal volume,
and respiratory distress syndrome as
Medical Subject Headings. We used a
sensitive filter for randomized controlled trials13 and imposed no lan866

guage restrictions. We hand-searched


conference proceedings (from 2004 to
2010) of the American Thoracic Society, the Society of Critical Care Medicine, the American Association of Respiratory Care, the European Society of
Intensive Care Medicine, the American College of Chest Physicians, and the
International Symposium on Intensive Care and Emergency Medicine. We
checked reference lists of identified articles, recent editorials, and related reviews and contacted experts for further eligible trials.
Two reviewers (M.B., M.M.) independently assessed trial eligibility based on
titles, abstracts, full-text reports, and further information from investigators as
needed. We requested the protocol, case
reportforms,andunediteddatabasesfrom
investigatorsofalleligibletrials.Datafrom
each trial were checked against reported
results,andquerieswereresolvedwiththe
correspondingprincipalinvestigator,trial
data manager, or statistician. Some of the
outcomesinthisreportmaydifferslightly
from those in published original study reports because we standardized outcome
definitions and data analyses.
To identify potential sources of bias,
we examined concealment of treatment
allocation, blinding of clinical outcome
assessments and data analyses, the proportion of patients lost to follow-up, and
early stopping prior to enrollment of the
target sample.14 We used the Grading of
Recommendations Assessment, Development and Evaluation system to rate the
overall quality of the evidence.15 In this
system, randomized clinical trials provide high-quality evidence unless limited by important risk of bias, imprecision, inconsistency, indirectness, or high
risk of publication bias.
Patient Outcomes and Subgroups

All investigators (with the exception of


D.T., who became involved later) provided feedback and authorized the final analysis plan prior to implementation. The primary outcome was hospital
mortality, measured to at least 60 days
in all eligible trials. Prespecified secondary outcomes were death before discharge from the intensive care unit,

JAMA, March 3, 2010Vol 303, No. 9 (Reprinted)

pneumothorax with need for chest tube


drainage in the first 28 days, death following pneumothorax with need for
chest tube drainage, time-to-unassisted breathing within the first 28 days,
days with unassisted breathing between day 1 and day 28, use of rescue
therapy (as defined in each trial
[eTable 1, available at http://www.jama
.com]), death following rescue therapy,
and the use of neuromuscular blockers, vasopressors, and corticosteroids.
We reexamined individual-patient
data on ratios of partial pressure of oxygen to fraction of inspired oxygen (FIO2)
from all included trials to classify patients as having or not having ARDS at
baseline, using a threshold PaO2:FIO2
value of 200 mm Hg or less to define
ARDS, as suggested by the AmericanEuropean Consensus Conference. A
priori, we hypothesized that patients with
more severe lung disease as reflected in
lower baseline lung compliance (estimated as tidal volume/[inspiratory plateau pressure PEEP]), lower PaO2 :
FIO2 ratio, presence of ARDS (PaO2:FIO2
ratio 200 mm Hg), and higher oxygenation index (defined as mean airway pressure100/[PaO2:FIO2 ratio])
would have more recruitable lung units
and thus derive more benefit from higher
levels of PEEP.1,4 We hypothesized less
benefit with higher PEEP in patients with
higher body mass index (calculated as
weight in kilograms divided by height in
meters squared) because of fewer recruitable lung units.
Statistical Analysis

All patients were analyzed in the study


group to which they were randomized. We used 2-sided t tests to compare respiratory variables during follow-up and likelihood ratio tests to
compare statistical models.
For the primary analysis of hospital
mortality, we calculated relative risks
(RRs) and 95% confidence intervals
(CIs) using log-binomial regression.16
We used a multivariable hierarchical
model with baseline patient characteristics (age, presence of severe sepsis, and
predicted probability of dying in hospital based on Acute Physiology and

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POSITIVE END-EXPIRATORY PRESSURE IN ACUTE LUNG INJURY AND ARDS

Chronic Health Evaluation II and Simplified Acute Physiology II scores,


which have similar accuracy17,18) as important prognostic factors as well as a
categorical trial variable, all as fixed
effects. To account for within- and between-hospital variability, we added recruiting hospitals within trials to the
model as a random effect (primary
analysis model).11
To examine lung compliance, body
mass index, PaO2:FIO2 ratio, presence
of ARDS, and oxygenation index as potential effect modifiers, we added each
of these baseline variables in turn to the
statistical model together with the corresponding interaction term with PEEP
group, both as fixed effects.
To compare in-hospital time to death
and time to unassisted breathing for the
groups treated with higher and lower
PEEP, we fitted Cox regression models
with the same covariables. We fitted corresponding linear and log-binomial regression models for continuous and binary secondary outcomes, respectively.
We explored heterogeneity in the treatment effect across trials using a likelihood ratio test that compared a more
complex model that additionally included interaction terms between treat-

ment group and trial as fixed effects with


a nested simpler model that excluded
those interaction terms.
As prespecified sensitivity analyses,
we calculated odds ratios and 95% CIs
from corresponding logistic regression models; conducted a Bayesian
random-effects analysis using noninformative priors19; and used multipleimputation techniques to impute missing covariable data.20 Each of these
analyses generated results very similar
to the ones obtained with the primary
analysis model using log-binomial
regression; we therefore focus this report on the results from the primary
analysis model. In post hoc exploratory analyses, we examined hospital
mortality by quintiles of baseline PaO2:
FIO2 ratio and oxygenation index and
investigated the stability of baseline
PaO2:FIO2 ratios by looking at the evolution of PaO2:FIO2 ratios at days 1, 3,
and 7 among patients with a baseline
PaO2:FIO2 ratio greater than 200 mm Hg.
We used Stata version 9.2 (StataCorp,
College Station, Texas) and SAS version 11.0 (SAS Institute Inc, Cary,
North Carolina) for statistical analysis, with P.05 as the nominal level of
statistical significance.

Figure 1. Trial Flow


1426 Potentially relevant randomized
controlled trials identified by search
of MEDLINE, EMBASE, and
Cochrane Central Register of
Controlled Trials plus hand search
of conference proceedingsa
1417 Excluded based on review of titles
and abstracts (did not compare
higher vs lower PEEP)
9 Retrieved for more detailed evaluation
5 Excluded
3 Control group did not use low
tidal volumesb
1 Between-group PEEP difference
<3 cm H2O during first 72 hc
1 Between-group PEEP difference
unclear during first 72 hd
4 Identified as potentially eligible
3 Included in primary meta-analysis of
individual-patient data
1 Included in sensitivity analysis only (did
not meet meta-analysis eligibility criteria)

PEEP indicates positive end-expiratory pressure.


a American Association of Respiratory Care, American
College of Chest Physicians, American Thoracic Society, European Society of Intensive Care Medicine,
International Symposium on Intensive Care and
Emergency Medicine, Society of Critical Care Medicine.
b Lower PEEP groups received ventilation with traditionally high volumes (9-14 mL/kg).
c Small trial (N=57 patients).
d Small trial (N=30 patients); principal investigator did
not reply to queries.

Table 1. Characteristics of Included Trials


Trial
Characteristic
Inclusion criteria
Recruitment period
Recruiting hospitals (country)
Patients randomized to
higher vs lower PEEP
Validity
Concealed allocation
Follow-up for primary
outcome, %
Blinded data analysis
Stopped early
Experimental intervention

Control intervention

Ventilator procedures

ALVEOLI,8 2004
Acute lung injury with PaO2:FIO2 300 a
1999-2002
23 (United States)
276 vs 273

LOVS,9 2008
Acute lung injury with PaO2:FIO2 250 a
2000-2006
30 (Canada, Australia, Saudi Arabia)
476 vs 509 b

EXPRESS,10 2008
Acute lung injury with PaO2:FIO2 300 a
2002-2005
37 (France)
385 vs 383 c

Yes
100

Yes
100

Yes
100

Yes
Yes
Yes
Stopped for perceived futility
No
Stopped for perceived futility
PEEP as high as possible without increasing
Higher PEEP according to FIO2 chart, recruit- Higher PEEP according to FIO2 chart, rement maneuvers for first 80 patients
quired plateau pressures 40 cm H2O,
the maximum inspiratory plateau presrecruitment maneuvers
sure 28-30 cm H2O
Conventional PEEP according to FIO2 chart, Conventional PEEP according to FIO2 chart, Conventional PEEP (5-9 cm H2O) to meet
required plateau pressures 30 cm H2O,
required plateau pressures 30 cm H2O,
oxygenation goals
no recruitment maneuvers
no recruitment maneuvers
Target tidal volumes of 6 mL/kg of predicted body weight; plateau pressures 30 cm H2O (with exception as above); respiratory rate 35/
min, adjusted to achieve arterial pH 7.30-7.45; ventilator mode: volume-assist control (except higher PEEP group in LOVS required
pressure control); oxygenation goals: PaO2 55-80 mm Hg and SPO2 88%-95%; standardized weaning)

Abbreviations: ALVEOLI, Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury; EXPRESS, Expiratory Pressure Study; FIO2, fraction of inspired
oxygen; LOVS, Lung Open Ventilation to Decrease Mortality in the Acute Respiratory Distress Syndrome; PEEP, positive end-expiratory pressure; SPO2, oxygen saturation.
a Acute lung injury defined according to the American-European Consensus Conference.12
b Includes 2 patients for whom consent was withdrawn prior to protocol initiation, without patient, family, and caregivers being aware of group assignment (ie, 983 patients analyzed).
c Includes 1 patient for whom consent was withdrawn prior to protocol initiation, without patient, family, and caregiver awareness of assignment (ie, 767 patients included in the analysis).

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POSITIVE END-EXPIRATORY PRESSURE IN ACUTE LUNG INJURY AND ARDS

RESULTS
Three trials, including 2299 patients, met
our eligibility criteria (FIGURE 1). In the
Assessment of Low Tidal Volume and
Elevated End-Expiratory Pressure to
Obviate Lung Injury (ALVEOLI) trial
(NCT00000579)8 and the Lung Open
Ventilation to Decrease Mortality in the
Acute Respiratory Distress Syndrome
(LOVS) study (NCT00182195), 9
PEEP levels were titrated to oxygenation using similar PEEP:FIO2 charts
(TABLE 1). The experimental strategy
in the Expiratory Pressure Study
(EXPRESS) (NCT00188058) 1 0 titrated PEEP levels based on measurements of plateau pressure, regardless of
the effect on oxygenation. Control strategies were similar in the ALVEOLI and
LOVS studies, which allowed appre-

ciably higher control levels of PEEP


than in the EXPRESS study. A fourth
trial, the Esophageal Pressure Directed Ventilation (EPVENT) study
(NCT00127491),21 did not explicitly
aim to compare higher with lower PEEP
levels and applied the allocated treatment for only 72 hours (eTables 2 and
3). In that trial, investigators titrated
PEEP levels in the experimental group
according to estimates of transpulmonary pressure, measured with an esophageal balloon. A sensitivity analysis including this trial did not change results
appreciably (eTable 4). The methodological quality of included trials was
high (Table 1). All trials concealed randomization, achieved complete follow-up for hospital mortality, and used
blinded data analysis.

The higher and lower PEEP groups


were similar at baseline with respect to
important prognostic features
(TABLE 2). Mean tidal volumes during
the study were close to 6 mL/kg of predicted body weight in both groups of
all 3 trials (TABLE 3). In the higher PEEP
group, PEEP and plateau pressure levels were considerably higher at each
point, and oxygenation was significantly better, as reflected in lower FIO2
values.
Among the prespecified potential
effect modifiers, there was a statistically significant interaction only for the
presence of ARDS at baseline (P=.02).
TABLE 4 therefore presents outcomes
for all patients and for those with and
without ARDS. Overall, the difference
in hospital mortality between the higher

Table 2. Baseline Characteristics of Included Patients


Characteristic
Age, mean (SD), y
Women, No. (%)
Body mass index, mean (SD) a
Days in ICU prior to randomization, median (IQR), d
Days intubated prior to randomization, median (IQR), d
Probability of death from APACHE II or SAPS II scores, median (IQR)
No. of organ failures in addition to respiratory failure, median (IQR) b
Respiratory measures, mean (SD)
PaO2:FIO2, mm Hg c
PaO2:FIO2 200 mm Hg, No. (%)
Oxygenation index, median (IQR) d
Set PEEP, cm H2O
Plateau pressure, cm H2O
Respiratory rate, breaths/min
Minute ventilation, L/min
Tidal volume, mL/kg of predicted body weight
Estimated respiratory system compliance, mL/cm H2O e
Cause of lung injury, No. (%) f
Pneumonia
Aspiration
Severe sepsis, including septic shock
Multiple transfusions
Acute pancreatitis
Multiple trauma
Other g

Higher PEEP (n = 1136)


56 (17) [n = 1136]
437 (38) [n = 1136]
27.1 (6.3) [n = 1024]
1 (1-3) [n = 1136]
1 (1-2) [n = 1136]
49 (29-70) [n = 1133]
1 (1-2) [n = 1123]

Lower PEEP (n = 1163)


56 (17) [n = 1163]
455 (39) [n = 1163]
26.9 (6.6) [n = 1038]
2 (1-3) [n = 1163]
1 (1-2) [n = 1163]
49 (29-70) [n = 1160]
1 (1-2) [n = 1149]

146 (56) [n = 1135]


951 (84) [n = 1135]
11.4 (8.2-16.8) [n = 989]
9.9 (4.0) [n = 1135]
26.7 (6.4) [n = 915]
23.1 (6.6) [n = 1133]
11.6 (3.2) [n = 1122]
8.0 (1.9) [n = 1107]
32.7 (14.9) [n = 909]

148 (60) [n = 1161]


941 (81) [n = 1161]
11.1 (7.7-17.0) [n = 1009]
9.7 (3.8) [n = 1160]
26.3 (6.6) [n = 899]
23.2 (6.7) [n = 1160]
11.7 (3.6) [n = 1151]
8.0 (2.0) [n = 1135]
32.6 (13.7) [n = 892]

567 (50)
214 (19)
595 (52)
71 (6.3)
37 (3.3)
60 (5.3)
146 (13)

578 (50)
247 (21)
628 (54)
74 (6.4)
48 (4.1)
73 (6.3)
119 (10)

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; ICU, intensive care unit; IQR, interquartile range; PEEP, positive end-expiratory pressure; SAPS II,
Simplified Acute Physiology Score II.
a Calculated as weight in kilograms divided by height in meters squared.
b Dichotomized Brussels Score as used in the Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury study;22 circulatory failure was defined
as systolic blood pressure of 90 mm Hg or less or the need for treatment with any vasopressor; coagulation failure as platelet count of 50 000 platelets/mm3 or less; hepatic failure
as serum bilirubin concentration greater than 5.9 mg/dL (100 mol/L); renal failure as serum creatinine concentration greater than 3.4 mg/dL (300 mol/L); and neurologic failure
as Glasgow Coma Scale score of 9 or less.
c Includes altitude adjustment for patients from Colorado ([760/635]PaO :FIO2) and Utah ([760/642]PaO :FIO ); for 25 ALVEOLI patients with missing PaO :FIO values at ven2
2
2
2
2
tilation change, PaO2:FIO2 values from the screening form of the same day were used.
d Oxygenation index was calculated as mean airway pressure100/(PaO :FIO ).
2
2
e Respiratory system compliance was calculated as tidal volume/(inspiratory plateau pressurePEEP).
f Individual patients could have more than 1 cause of lung injury.
g Includes drug overdose, prolonged shock, burn injury, inhalation injury, intra-alveolar hemorrhage, cardiopulmonary bypass, near drowning, vasculitis, and heat stroke.

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POSITIVE END-EXPIRATORY PRESSURE IN ACUTE LUNG INJURY AND ARDS

and lower PEEP groups was not statistically significant (32.9% vs 35.2%; RR,
0.94; 95% CI, 0.86-1.04; P=.25). However, we found a statistically significant reduction of death in the intensive care unit for patients allocated to
the higher PEEP group (28.5% vs
32.8%; RR, 0.87; 95% CI, 0.78-0.97;
P = .01). Clinicians instituted rescue
therapies for profound hypoxemia less
frequently in patients with higher PEEP,
and the rate of deaths following rescue therapy was also significantly lower.
The groups did not differ significantly
in rates of pneumothorax, hospital
deaths following pneumothorax, use of
vasopressors, or number of days with
unassisted breathing during the first 28
days of study.
For patients with ARDS at baseline,
those in the higher PEEP group were
less likely to die in hospital (34.1% vs
39.1%; RR, 0.90; 95% CI, 0.81-1.00;
P=.049) and more likely to achieve unassisted breathing earlier (hazard ratio, 1.16; 95% CI, 1.03-1.30; P=.01; proportions at 28 days, 64.3% vs 57.8%);
for patients without ARDS at baseline,
the RR for death in hospital with higher
vs lower PEEP was 1.37 (95% CI, 0.981.92; P=.07; 27.2% vs 19.4%) and the
hazard ratio for time to unassisted
breathing was 0.79 (95% CI, 0.62-

0.99; P = .04; proportions at 28 days,


70.1% vs 80.9%) (Table 4, FIGURE 2).
Stratified results for other secondary efficacy outcomes consistently
showed benefit from higher PEEP for
patients with ARDS, with less benefit
or even harm from higher PEEP for patients without ARDS (Table 4). A sensitivity analysis including the EPVENT
trial generated RRs for hospital mortality of 0.88 (95% CI, 0.79-0.98; P=.02;
33.9% vs 39.0%) for patients with ARDS
and 1.29 (95% CI, 0.91-1.83; P = .14;
26.5% vs 19.4%) for patients without
ARDS.
When we explored heterogeneity in
the treatment effect for hospital mortality across trials, there was no evidence for an interaction (P=.59 by likelihood ratio test). Analyses of hospital
mortality by quintiles of baseline PaO2:
FIO2 ratio suggest a threshold effect
around a PaO2:FIO2 ratio of 200 mm Hg
rather than a progressive increase in the
effect of higher vs lower PEEP as PaO2:
FIO2 ratio decreases (eFigure 1). This
is compatible with the pattern seen for
quintiles of baseline oxygenation index (eFigure 2). Exploring the stability of baseline PaO2:FIO2 ratios, we found
that in 50% of patients with acute lung
injury and not ARDS at baseline, the
PaO2:FIO2 ratio consistently remained

above the critical threshold of 200


mm Hg at days 1, 3, and 7 after randomization.
Use of neuromuscular blockers, corticosteroids, and vasopressors was similar for the groups treated with higher
and lower PEEP. About 45% of patients received neuromuscular blockers, 45% received corticosteroids, and
65% received vasopressors for a median of 3, 7, and 4 days, respectively.
COMMENT
This systematic review and metaanalysis of individual-patient data from
randomized trials comparing higher with
lower PEEP levels in 2299 patients with
acute lung injury showed, overall, no statistically significant difference in hospital mortality. Results suggest, however,
differences in the response to higher
PEEP for those with ARDS vs those without ARDS at baseline. In patients with
ARDS, higher levels of PEEP were associated with a relative mortality reduction of 10% (absolute difference, 4%;
number needed to treat, 25). In contrast, patients with acute lung injury but
without ARDS may not benefit or may
actually experience harm from higher
PEEP levels. The results for patients with
ARDS do not exclude a small increased
risk of pneumothorax (absolute risk dif-

Table 3. Respiratory Variables During First Week of Treatment


Mean (SD)
Day 1

Day 3

Day 7

Higher
PEEP

Lower
PEEP

P
Value

Higher
PEEP

Lower
PEEP

P
Value

Higher
PEEP

Lower
PEEP

P
Value

Tidal volume, mL/kg of


predicted body weight

6.3 (1.0)
[n = 1051]

6.3 (0.8)
[n = 1051]

.33

6.3 (1.0)
[n = 793]

6.3 (1.0)
[n = 852]

.47

6.5 (1.4)
[n = 443]

6.4 (1.3)
[n = 494]

.25

Plateau pressure, cm H2O

29 (5.4)
[n = 1043]

23 (5.6)
[n = 991]

.001

27 (5.6)
[n = 781]

23 (5.9)
[n = 825]

.001

27 (6.2)
[n = 408]

24 (6.9)
[n = 443]

.001

FIO2

0.51 (0.18)
[n = 1053]

0.61 (0.19)
[n = 1051]

.001

0.44 (0.15)
[n = 812]

0.56 (0.18)
[n = 862]

.001

0.45 (0.15)
[n = 502]

0.54 (0.19)
[n = 550]

.001

PEEP, cm H2O

15.3 (3.4)
[n = 1053]

9.0 (3.1)
[n = 1051]

.001

13.3 (4.3)
[n = 812]

8.2 (3.0)
[n = 863]

.001

10.8 (5.0)
[n = 503]

7.8 (3.3)
[n = 548]

.001

Oxygenation index a

13.2 (8.7)
[n = 949]

12.7 (7.8)
[n = 944]

.16

11.2 (7.0)
[n = 705]

11.6 (7.1)
[n = 755]

.29

11.2 (7.1)
[n = 392]

11.8 (8.4)
[n = 421]

.34

PaO2, mm Hg

96 (38)
[n = 1024]

83 (29)
[n = 1026]

.001

87 (31)
[n = 792]

82 (28)
[n = 835]

.001

84 (25)
[n = 484]

83 (26)
[n = 532]

.41

PaCO2, mm Hg

44 (11)
[n = 1025]

44 (11)
[n = 1026]

.42

44 (9.9)
[n = 792]

44 (11)
[n = 835]

.68

45 (12)
[n = 485]

46 (12)
[n = 532]

.06

Arterial pH

7.35 (0.09)
[n = 1025]

7.36 (0.09)
[n = 1026]

.02

7.38 (0.08)
[n = 793]

7.38 (0.08)
[n = 836]

.49

7.41 (0.08)
[n = 485]

7.40 (0.08)
[n = 532]

.08

Variable

Abbreviations: FIO2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure.


a Calculated as mean airway pressureFIO 100/PaO .
2
2

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POSITIVE END-EXPIRATORY PRESSURE IN ACUTE LUNG INJURY AND ARDS

ference, 1.6%) with higher PEEP, but differences in fatal consequences from such
barotrauma are unlikely (absolute risk
difference, 0.6%; RR, 1.20; 95% CI, 0.791.81). Otherwise, we found no evidence suggesting serious adverse effects associated with higher PEEP in
patients with ARDS.
The strengths of this review include
an explicit study protocol and analysis
plan; access to trial protocols, case report forms, and complete, unedited data
sets; standardized outcome definitions
across trials (except for rescue therapies); and analyses based on the intention-to-treat principle. To minimize the
risk of overfitting and data-driven associations, we prespecified a limited number of prognostic factors and potential
effect modifiers for our statistical models.23 We calculated RRs adjusted for im-

portant prognostic factors using logbinomial models 16 and allowed for


potential clustering effects by using random effects for recruiting hospitals.24 Our
results proved robust in sensitivity analyses applying alternate statistical approaches. We followed current recommendations for subgroup analyses in
meta-analysis of individual-patient data,25
thereby overcoming limitations of metaanalyses using aggregated data.26-29 All included trials met high methodological
quality standards (concealed randomization, explicit study protocols, and
complete follow-up) and systematically
collected data on important, potential adverse effects of high PEEP administration by routinely documenting deaths,
pneumothorax, use of vasopressors (hemodynamic instability) and rescue therapies (refractory hypoxemia), and dura-

tion of mechanical ventilation and


intensive care. An independent data and
safety monitoring committee was established to monitor and protect the safety
of participants in each trial. The 3 major trials included 90 multidisciplinary
intensive care units with international
representation; these features enhance
the generalizability of our findings.
The subgroup effect for ARDS at
baseline meets all criteria for a credible subgroup analysis.30 We found a
large and statistically significant (P=.02
for interaction) difference in RRs that
was consistent across individual trials
and efficacy outcomes. The hypothesis was generated a priori and was one
of a small number tested. Exploring the
effect of higher vs lower PEEP across
quintiles suggests a threshold effect,
rather than a progressive increase in

Table 4. Clinical Outcomes in All Patients and Stratified by Presence of ARDS at Baseline
All Patients

With ARDS

No. (%)

Outcomes

Higher
Lower
PEEP
PEEP
(n = 1136) (n = 1163)

Without ARDS

No. (%)
Higher
Adjusted RR
P
PEEP
a
(95% CI)
Value (n = 951)

Lower
PEEP
(n = 941)

No. (%)
Higher
Lower
Adjusted RR
P
PEEP
PEEP
a
(95% CI)
Value (n = 184) (n = 220)

Adjusted RR
P
(95% CI) a
Value

Death in hospital

374 (32.9) 409 (35.2)

0.94
(0.86 to 1.04)

.25

324 (34.1) 368 (39.1)

0.90
(0.81 to 1.00)

.049 50 (27.2) 44 (19.4)

1.37
(0.98 to 1.92)

.07

Death in ICU b

324 (28.5) 381 (32.8)

0.87
(0.78 to 0.97)

.01

288 (30.3) 344 (36.6)

0.85
(0.76 to 0.95)

.001 36 (19.6) 37 (16.8)

1.07
(0.74 to 1.55)

.71

87 (7.7)

75 (6.5)

1.19
(0.89 to 1.60)

.24

80 (8.4)

64 (6.8)

1.25
(0.94 to 1.68)

.13

7 (3.8)

11 (5.0)

0.72
(0.37 to 1.39)

.33

43 (3.8)
Death after
pneumothorax c

40 (3.5)

1.11
(0.73 to 1.69)

.63

41 (4.3)

35 (3.7)

1.20
(0.79 to 1.81)

.39

2 (1.1)

5 (2.3)

0.44
(0.08 to 2.35) g

.34

.10

12 (0-21)

1.22
(0.39 to 2.05) e

.004 17 (0-23) 19 (5.5-24)

1.74
(3.60 to 0.11) e

.07

Pneumothorax
between day
1 and day 28 c

13 (0 to 22) 11 (0 to 21)
0.64
Days with
(0.12 to 1.39) e
unassisted
breathing
between day 1
and day 28,
median (IQR) d
Total use of rescue 138 (12.2) 216 (18.6)
therapiesf
Death after rescue
therapy f
Use of
vasopressors

85 (7.5)

132 (11.3)

722 (63.6) 759 (65.3)

7 (0-20)

0.64
.001 130 (13.7) 200 (21.3)
(0.54 to 0.75)

0.63
.001
(0.53 to 0.75)

8 (4.4)

16 (7.3)

0.60
(0.25 to 1.43) g

.25

0.65
.001
(0.52 to 0.80)

0.66
.001
(0.52 to 0.82)

3 (1.6)

8 (3.6)

0.37
(0.10 to 1.46) g

.15

0.92
(0.56 to 1.50) g

.72

0.93
(0.75 to 1.14) g

.49

82 (8.6)

124 (13.2)

627 (65.9) 647 (68.8)

0.90
(0.72 to 1.13) g

.37

95 (51.6) 111 (50.5)

Abbreviations: ARDS, acute respiratory distress syndrome; CI, confidence interval; ICU, intensive care unit; IQR, interquartile range; PEEP, positive end-expiratory pressure; RR,
relative risk.
a Multivariable regression with the outcome of interest as dependent variable; PEEP group, age, probability of dying in hospital derived from prognostic scores at baseline, severe
sepsis at baseline, and trial as independent variables; and hospital as a random effect.
b Patients who died before being discharged from the intensive care unit for the first time up to day 60.
c Defined as the need for chest tube drainage.
d Median number of days of unassisted breathing to day 28 after randomization, assuming a patient survives and remains free of assisted breathing for at least 2 consecutive
calendar days after initiation of unassisted breathing.
e Coefficient from a corresponding linear regression model using the same independent variables and random effect as the above-described log-binomial model; for example, a
coefficient of 1.22 means that patients in the group treated with higher PEEP have, on average, 1.22 days more of unassisted breathing during the first 28 days compared with
patients in the group treated with lower PEEP.
f As defined in each trial; rescue therapies included in the Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury and the Lung Open Ventilation to Decrease Mortality in the Acute Respiratory Distress Syndrome studies: inhaled nitric oxide, prone ventilation, high-frequency oscillation, high-frequency jet ventilation,
extracorporeal membrane oxygenation, partial liquid ventilation, and surfactant therapy. Rescue therapies included in the Expiratory Pressure Study: prone ventilation, inhaled
nitric oxide, and almitrine bismesylate.
g Adjusted odds ratio substitutes for relative risk, because the corresponding log-binomial model did not converge.

870

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POSITIVE END-EXPIRATORY PRESSURE IN ACUTE LUNG INJURY AND ARDS

and mortality following rescue therapy


in the higher PEEP group. Moreover,
we were unable to standardize the use
of rescue therapies across trials, because they depended mainly on local
settings and preferences of local intensivists (eTable 1). Problems with standardization of outcomes for metaanalyses of individual-patient data could
be overcome by international collaboration with coordinated protocols of individual trials. We wrote the protocol
for the present study after the publication of ALVEOLI results but before the
publication of those from LOVS and
EXPRESS; none of the investigators
knew the results from all 3 trials.

The trials in this review used different approaches to determine PEEP


level. In the EXPRESS trial, PEEP levels were titrated according to bedside
measurements of inspiratory plateau
pressure (eAppendix). In the ALVEOLI
and LOVS trials, PEEP titration was
linked to oxygenation. The EPVENT
trial explored a further option for PEEP
titration by estimating transpulmonary pressure with the use of esophageal balloon catheters. This metaanalysis of individual-patient data is
unable to provide guidance on the optimal method of titrating PEEP, since
the type of PEEP titration is completely confounded with all the other

Figure 2. Time to Death in Hospital and Time to Unassisted Breathing for Higher and Lower
Positive End-Expiratory Pressure (PEEP) Stratified by Presence of Acute Respiratory Distress
Syndrome (ARDS) at Baseline
In-hospital time to death
Patients with ARDS

Patients without ARDS

1.0

Probability

0.8
0.6
HR, 1.32 (95% CI, 0.87-2.00); P = .20

HR, 0.85 (95% CI, 0.73-0.99); P = .03


0.4
Higher PEEP
Lower PEEP

0.2
0
0

20

40

60

Days After Randomization


No. at risk
Higher PEEP 949
Lower PEEP 939

760
723

693
649

20

40

60

Days After Randomization


666
619

183
219

158
196

148
186

144
183

Time to unassisted breathing


Patients with ARDS

Patients without ARDS

1.0
HR, 1.16 (95% CI, 1.03-1.30); P = .01

0.8

Probability

effect as PaO2:FIO2 ratio decreases or as


the oxygenation index increases
(eFigures 1 and 2). This may explain
why examining PaO2:FIO2 ratio and oxygenation index as linear effect modifiers did not yield significant interactions.
The ARDS interaction is supported by
external evidence. Earlier preclinical and
clinical trials providing indirect evidence that higher PEEP strategies improve survival were restricted to animal models of ARDS5,31 and to patients
with severe32 or persistent33 ARDS. Moreover, a recent cohort study in patients
with acute lung injury or ARDS found
that the effect of PEEP on lung recruitment was closely associated with the percentage of potentially recruitable lung
as determined by computed tomography.4 Patients with ARDS have more
lung edema and thus greater recruitability than patients with acute lung injury
but without ARDS.1 In patients with
ARDS, higher levels of PEEP may prevent atelectasis, recruit already collapsed alveolar units, and reduce pulmonary damage by avoiding the cyclical
opening and collapse of alveoli in those
patients.1,34,35 Patients with ARDS treated
with lower PEEP levels may develop
worsening lung injury, as suggested by
our findings on refractory hypoxemia
and use of rescue therapies.
This study also has limitations. Although our subgroup finding for patients with ARDS meets common credibility criteria, we cannot rule out the
possibility of a chance finding. Moreover, although we pooled the data of all
eligible trials on the topic, our study had
limited statistical power. In a post hoc
calculation, we estimated that our primary analysis had a power of 72% to
detect a 5% absolute risk reduction in
hospital mortality (2-sided =.05). The
power of our meta-analysis of individual-patient data would have been
greater had none of the 3 trials stopped
early for futility.
Because caregivers were not blinded
to allocated PEEP strategies, differing
thresholds for rescue therapy in the
high and low PEEP groups could explain the lower use of rescue therapies

0.6
0.4
0.2
HR, 0.79 (95% CI, 0.62-0.99); P = .04
0
0

14

21

28

Days After Randomization


No. at risk
Higher PEEP 949
Lower PEEP 939

653
589

408
328

283
207

14

21

28

Days After Randomization


209
142

183
219

145
179

95
123

60
83

44
63

Cox regression models adjusting for age, probability of death in hospital derived from prognostic scores at baseline, severe sepsis at baseline, and trial. For the analysis of time to unassisted breathing, data were censored at the
time of death because time to death was modeled separately and a sensitivity analysis without censoring at death
yielded very similar results. Additionally including the Esophageal Pressure Directed Ventilation trial (n=61) revealed adjusted hazard ratios (HRs) for hospital mortality of 0.83 (95% confidence interval [CI], 0.71-0.96; P=.01;
33.9% vs 39.0%) for patients with ARDS (n=1941) and 1.26 (95% CI, 0.84-1.88; P=.27; 26.5% vs 19.4%) for
patients without ARDS (n=416). Corresponding hazard ratios for time to unassisted breathing were 1.14 (95%
CI, 1.02-1.28; P=.02; proportions at 28 days, 64.2% vs 58.0%) for patients with ARDS (n=1941) and 0.80 (95%
CI, 0.64-1.01; P=.06; proportions at 28 days, 70.4% vs 79.7%) for patients without ARDS (n=416).

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871

POSITIVE END-EXPIRATORY PRESSURE IN ACUTE LUNG INJURY AND ARDS

structural differences among the trials


(eg, differences in study populations or
the use of recruitment maneuvers) that
are captured in the trial effect, which
is a subject that lends itself to further
research. Results of this review, however, provided no suggestion of differences in effect across the 3 major trials
(P=.59 for interaction between trial and
treatment).
Analyses involving lung compliance are limited by missing data and indirect calculations. Plateau pressures,
in particular, are often difficult to measure reliably, which is reflected in a relatively high proportion of missing plateau pressures at baseline (485/2299
[21%] missing). However, sensitivity
analyses using multiple imputation of
missing compliance values were consistent with results from the complete
case analysis. Analyses investigating
body mass index as an effect modifier
were limited by the systematic exclusion of patients with morbid obesity (actual body weight exceeding 1 kg/cm of
height) in all 3 trials.
Current definitions for ARDS do not
take into account the levels of applied
PEEP; ARDS cohorts may, therefore, include patients with varying levels of
lung injury.12,36 Moreover, PaO2:FIO2 ratios typically vary over time. Although these limitations might reduce the usefulness of our subgroup
effect for a diagnosis of ARDS at baseline, further explorations supported the
subgroup finding. Patients with acute
lung injury but without ARDS at baseline had, in general, a better clinical
prognosis throughout the first 2
months, with lung injury never evolving to ARDS in half of these patients.
Using the Grading of Recommendations Assessment, Development and
Evaluation system, we have classified
the evidence suggesting that higher levels of PEEP are associated with lower
mortality for patients with ARDS as of
high quality. Nevertheless, our confidence in this conclusion is limited by
the fact that it is a subgroup result with
borderline statistical significance
(eTable 5). Including the EPVENT trial
in a sensitivity analysis improved the
872

precision of this finding (individual subgroup P=.02). The wide CI around the
estimated RR of mortality in patients
without ARDS warrants a rating of moderate-quality evidence.
Without considering the subgroup
analysis definitive, and while awaiting
further evidence on the topic, our results may have the following clinical implications. The potentially lower hospital mortality and the absence of increased
serious adverse events associated with
higher PEEP levels in patients with ARDS
support the safety of higher PEEP in
these patients. For this purpose, clinicians could titrate PEEP as described in
the 3 major trials in this review (eAppendix). For patients without ARDS, the
results lack statistical power; still, the
95% CI of 0.98-1.92 for hospital mortality in patients without ARDS indicates that an RR reduction of 2% (0.4%
absolute reduction) associated with
higher PEEP is plausible but that larger,
important risk reductions are unlikely.
Clinicians should bear in mind the possible harm when considering the use of
higher PEEP in patients with less severe acute lung injury.
In addition to its clinical messages,
our work provides lessons for clinical
trialists. Single trials, even those powered for moderate effects, will often
fail to provide definitive answers.
Such trials will almost invariably be
unable to meaningfully address possible subgroup effects. A culture of
international collaboration, ideally
using coordinated trial protocols and
conducting prospective meta-analysis
of individual-patient data, is required
to maximize the clinical information
from expensive and arduous clinical
trials. With a view to ultimately using
individual trial data to contribute to
such a larger effort, investigators
should also keep this option in mind
when they consider stopping trials
early for futility.37
In summary, this systematic review
and meta-analysis of individualpatient data suggests that higher levels of PEEP may be associated with
lower hospital mortality in patients
meeting criteria for ARDS. Our results

JAMA, March 3, 2010Vol 303, No. 9 (Reprinted)

further suggest that such a benefit is unlikely in patients with less severe lung
injury; indeed, a strategy of treating
these patients using high PEEP levels
may be harmful.
Author Affiliations: Departments of Clinical Epidemiology and Biostatistics (Drs Briel, Meade, Walter, Pullenayegum, Zhou, Cook, Lamontagne, and Guyatt and
Ms Bhatnagar) and Medicine (Drs Meade and Guyatt), McMaster University, Hamilton, Ontario, Canada;
Basel Institute for Clinical Epidemiology, University Hospital Basel, Basel, Switzerland (Dr Briel); University Hospital Angers, Angers, France (Dr Mercat); Division of Pulmonary and Critical Care Medicine, Johns Hopkins
University, Baltimore, Maryland (Dr Brower); Department of Anesthesia, Critical Care, and Pain Medicine,
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts (Dr Talmor); University of Toronto, Toronto, Ontario, Canada (Drs Slutsky
and Stewart); Medical ICU, University Hospital Albert
ChenevierHenri Mondor, INSERM Unit 955 and University Paris-Est, Creteil, France (Dr Brochard); University Hospital Charles Nicolle and UPRES EA Unit 3830,
Rouen, France (Dr Richard); and University of Sherbrooke, Sherbrooke, Quebec, Canada (Dr Lamontagne).
Author Contributions: Dr Briel had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Briel, Meade, Mercat,
Slutsky, Brochard, Lamontagne, Guyatt.
Acquisition of data: Briel, Meade, Mercat, Brower,
Talmor, Slutsky, Brochard, Richard, Bhatnagar, Guyatt.
Analysis and interpretation of data: Briel, Meade,
Brower, Walter, Pullenayegum, Zhou, Cook, Brochard,
Stewart, Guyatt.
Drafting of the manuscript: Briel, Meade, Walter,
Guyatt.
Critical revision of the manuscript for important intellectual content: Meade, Mercat, Brower, Talmor,
Slutsky, Pullenayegum, Zhou, Cook, Brochard, Richard,
Lamontagne, Bhatnagar, Stewart.
Statistical analysis: Briel, Walter, Pullenayegum, Zhou.
Obtained funding: Briel, Meade, Guyatt.
Administrative, technical, or material support: Briel,
Brower, Cook, Bhatnagar, Stewart.
Study supervision: Briel, Meade, Guyatt.
Financial Disclosures: Dr Mercat and Dr Richard reported receiving a research grant from General Electric. Dr Slutsky reported receiving consulting fees from
Maquet Medical. Dr Brochard reported that his research laboratory has received research grants for the
conduct of clinical trials during 2006, 2007, and 2008
from Drger, General Electric, Maquet, Viasys, and
Starmed. No other authors reported financial disclosures.
Funding/Support: The study was funded in part by a
grant from the Canadian Intensive Care Foundation.
Dr Briel is supported by a scholarship from the Swiss
National Science Foundation (PASMA-112951/1) and
the Roche Research Foundation. Dr Cook is a Canada
Research Chair of the Canadian Institutes for Health
Research.
Role of the Sponsor: The funding sources had no role
in the design and conduct of the study; the collection, analysis and interpretation of the data; or the
preparation, review, or approval of the manuscript.
Online-Only Material: eTables 1 through 5, eFigures 1 and 2, and the eAppendix are available at http:
//www.jama.com.
Additional Contributions: We thank Jean Marie Chretien, MSc (Centre Hospitalier Universitaire dAngers,
Angers, France), David Schoenfeld, PhD, and Katherine Husk, BSc (both of Massachusetts General Hospital, Boston), for assisting with data queries. We are
grateful to Ramon Saccilotto, MD (Basel Institute for

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POSITIVE END-EXPIRATORY PRESSURE IN ACUTE LUNG INJURY AND ARDS


Clinical Epidemiology and Biostatistics, Basel, Switzerland), and Diane Heels-Ansdell, MSc (Department for Clinical Epidemiology and Biostatistics,
McMaster University, Hamilton, Ontario, Canada), for
their technical assistance during data analysis. None
of these persons received any compensation for their
help with this study.

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